Bone morphogenetic protein (BMP) signaling has been implicated in several processes during embryonic development and in adult tissue homeostasis. BMPs provide critical signals for determining cell fate, embryonic patterning, osteogenesis, chondrogenesis, iron homeostasis and are regulators of endothelial cell proliferation, migration and tube formation. Genetic studies in human and in mouse show that perturbations in BMP signaling lead to various diseases. Mutations in BMP type II and type I receptors have been linked to pulmonary arterial hypertension (PAH) (Long et al. Nature Medicine 21:777-784, 2015), and hereditary hemorrhagic telangiectasia (HHT) (Tillet et al. Front. Genet. 8(5): 456, 2015; Wang et al. Genes & Diseases 1:87-105, 2014), also known as Osler-Weber-Rendu disease and Osler-Weber-Rendu syndrome, respectively. Deficiency of BMP signaling is also involved in kidney injury, proteinuric diseases, and iron overload anemia (Sampath et al. (2017) Bone Morphogenetic Protein-7 and Its Role in Acute Kidney Injury and Chronic Kidney Failure; Vukicevic S., Sampath K. (eds) Bone Morphogenetic Proteins: Systems Biology Regulators; Progress in Inflammation Research. Springer, Cham; Steinbicker et al. Blood 118(15): 4224-4230).
Further, HHT is an inherited autosome dominant vascular dysplasia affecting 1:5000/8000 people worldwide. Hallmark features include recurrent epistaxis (nosebleed) and/or chronic GI blood loss due to telangiectasias (small dilated blood vessels) of mucosal surfaces and arteriovenous malformations (AVM) in solid organs. Larger AVMs occur in lungs (40-60% of affected individuals), liver (40-70%), brain (10%) and spine (1%). Management of HHT has largely been procedural to control the symptoms. All mutations identified in HHT patients to date affect the BMP pathway, including Endoglin (ENG) (HHT1, ˜45%), Acvrl1 (ALK1) (HHT2, ˜42%), and SMAD4 (Juvenile Polyposis & HHT, ˜1-2%). These mutations result in haploinsufficiency of functional proteins, which cause the pathophysiology of HHT manifested as fragile vessels, capillary overgrowth and numerous AVMs. Potentiating BMP signaling would normalize the pathway signaling in vascular cells of HHT patients, to prevent the formation of new lesions and support involution of existing telangiectasias.
BMP-7 is expressed in all parts of the normal kidney parenchyma, being highest in the epithelium of proximal tubules. It protects kidney against acute and chronic injury, inflammation and fibrosis. Diabetic nephropathy is the leading cause of chronic kidney disease. Clinical data from 30 patients with diabetic nephropathy (showing increased expression of BMP-7 at initial stages of diabetic nephropathy with subsequent decrease at advanced stage) highlights the role of BMP-7 in the protection of kidney structure and function (Ivanac-Jankovic et al. Acta Clin Croat. 54(2): 164-8, 2015).
FK506 is a potent BMP potentiator, as it displaces FKBP12 from BMP type I receptors, thus unblocking their phosphorylation site (Spiekerkoetter et al. J. Clin. Invest. 123(8):3600-3613, 2013). In addition, FK506 is an immunosuppressive 23-membered macrolide lactone natural product, and has been used clinically in solid organ transplants. FK506 inhibits calcineurin activity by a unique, small molecule-mediated, protein-protein interaction. FK506 binds to FKBP12, and this binary complex binds to calcineurin and blocks dephosphorylation of pNFAT in mammals leading to immunosuppression. (Nambu et al. Bioorganic & Medicinal Chemistry Letters 27: 2465-2471, 2017). However, pharmacologically, calcineurin inhibition by FK506 is not required to potentiate BMP signaling. (Dumont et al. J. Exp. Med. 176:751-760, 1992). The majority of clinical toxicities, including nephrotoxicity, of FK506 and FK506 analogs are associated with calcineurin inhibition. Therefore, calcineurin-sparing FK506 analogs should have an improved therapeutic index. As such, there remains a need for new treatments and therapies for renal diseases, HHT and other disorders related to BMP signaling deficiency that potentiate BMP signaling, but are calcineurin-sparing.